nEPHroProtEction, Part oF MULti-orGan ProtEction

ACE inhibitors and AII receptor blockers have a
hypotensive effect with subsequent renal, cardiac and
cerebroprotective actions. At the same time they exert
an antiproteinuric effect, mainly on renal blood flow.
Concomitantly, statins have a lipid-lowering effect
which acts protectively on the coronary cerebral and
renal blood supply.
Another approach is the association of multiple
drugs targeting different risk factors, resulting in
multiorgan protection. Thereby, complex protection
can be achieved, because many risk factors are shared
by the kidney, heart and brain. The most commonly
prescribed associations are:
- Single pill: aspirin, statin, 3 blood pressure
lowering drugs at half dosage, and folic acid as
proposed by Law et al. 25
- A super-pill: ACE inhibitors, ARBs, diuretics,
non-dihydropyridine calcium channel blockers. 26
- A combination of aspirin, lovastatin, lisinopril
which has been named ASTACE (aspirin, statin, ACE
inhibitor). 27
We will briefly summarize some of the drugs
with nephroprotective effect which possess cardiac,
neurological and also multiorgan protective actions.
These drugs also exert cytoprotective and molecular
protective effects.
ACE inhibitors and Angiotensin II receptor
blockers (ARB)
They exert actions on the vascular tree at the level
of different organs ensuring renal, cardiac and cerebral
protection. Blood pressure lowering is their main
action. These drugs have a cardioprotective effect by
improving cardiac function after myocardial infarction,
reducing cardiovascular morbidity and mortality as
shown in HOPE study. 22 A better effect on morbidity
and mortality has been reported with ARBs compared
to other hypotensive drugs at the same level of blood
pressure reduction. 28
ACE inhibitors and ARBs also demonstrated
neuroprotective action - prevention of stroke, and
nephroprotective effects - they slow the progression
of renal disease. 6
The antiproteinuric effect is produced by
lowering intraglomerular pressure and modification
of glomerular capillary permeability and increases
upon association to ARBs of ACE inhibitors. 29,30 They
have a nephroprotective effect in both hypertensive
and normotensive individuals, which could be partly
explained by the reduction of proteinuria. 31 ARBs have
a positive effect on renal fibrosis by collagen synthesis
blockade. 32
Treatment with statins
Their main action consists of blockade of
cholesterol synthesis, thereby exerting strong lipidlowering
effect. Besides, statins have pleiotropic
effects, such as the following: reduction of NFkB
activation, anti-inflammatory action, anti-oxidant
effect, hypotensive effect, by down regulation of AII
receptor type I, improvement of endothelial function
by means of up-regulating endothelial cell NO
synthase, reduction of reactive oxygen species in the
vascular wall, and antiproteinuric effect: cerivastatin has
been reported to reduce microalbuminuria in patients
with type II diabetes mellitus. 33 The blood pressure
lowering effect can contribute to the reduction of
albuminuria. The combination of statins with ACE
inhibitors diminishes glomerulosclerosis and protein
excretion in the Heymann nephritis model in rats,
while ACE-inhibitors or statin monotherapy has
limited effects. 34
HMG-CoA reductase inhibitors improve diabetic
nephropathy through pleiotropic effects in rats. 35
Lovastatin inhibits mesangial cell proliferation in
rats, while cerivastatin prevents ICAM 1 expression. 36
Statins selectively block LFA-1 mediated adhesion and
costimulation of lymphocytes.
Erythropoietin (EPO)
It is a cytokine mainly produced by the kidney with
stimulating effects on erythropoiesis. Furthermore,
eryhtropoietin demonstrated tissue-protective effects in
an experimental model of ischemic-induced neuronal,
retinal, cardiac and renal lesions. 37 With the exception
of its stimulating effect on erythropoiesis, the other
effects occur at increased concentrations which are
different from those therapeutically employed for the
correction of anemia.
The nephroprotective effect of EPO has been
demonstrated in the ischemia/reperfusion model in
rats and mice and is related to apoptosis.
The cardioprotective effect is produced by
EPO receptors. EPO prevents myocyte apoptosis;
apart from the effect on cardiac myocytes, it acts on
endothelial progenitors and on hematopoietic stem
cells. 18 EPO has cardioprotective actions in ischemia/
reperfusion injury in rats. 38 It reduces myocardial
infarction after ligation of coronary arteries in rats.
Experimental data in dogs have shown EPO to
reduce lethal arrhythmia and size of infarction. 39 EPO
induces myocardial neovascularization. Through
correction of anemia it leads to regression of left
ventricular hypertrophy in patients with predialytic
advanced CKD, as well as in dialysed hypertensive
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Gheorghe Gluhovschi et al 195